The most effective treatments for each of the addictive diseases probably will be based on a fundamental understanding of the biological bases of addictive diseases; the physiological as well as pharmacological effects of drugs of abuse and of agents used for the treatment of drug abuse or addiction; as well as on information about approaches to the management of the other medical and behavioral problems which may complicate treatment. Research activities will continue to identify and study the biological correlates of addictions, factors which affect treatment outcome and also the neurobiological bases of addiction. Pharmacological, metabolic, neuroendocrine, immunological, medical and behavioral problems which are present in addicts at time of entry to treatment, and which may complicate treatment, will be studied. Specific projects include: 1) further studies using conventional techniques of the disposition, metabolism, processing, and interaction of exogenous and endogenous opioids and their antagonists, as well as their related neuropeptides, along with development of novel techniques using laser desorption extended range matrix assisted mass spectrometry for qualitative and quantitative measurements of opioids, other neuropeptides, opiates, and opioid antagonists; 2) studies of the effects of selected drugs of abuse and treatment agents as well as selected neuropeptides, including dynorphin peptides, on neuroendocrine function, immune function, and on mood and behavior, and to study the relationship of atypical responsivity to induced stress, which we have previously observed in preliminary studies in both abstinent heroin addicts and cocaine addicts, to the clinical phenomena of craving and relapse; 3) further studies of the effects of cocaine, morphine, alcohol, and potential treatment agents using rodent models (rat, guinea pig and mouse), a) on opioid receptors, using techniques of quantitative autoradiography and other in vivo techniques, b) on opioid peptide gene expression by use of a modified sensitive technique of solution hybridization protection assay for quantitation of specific mRNA's, and c) measurement of neuropeptides and the processing of active neuropeptides using conventional and novel techniques under development; 4) use of the technique of microdialysis to study neurotransmitter and potential neuropeptide release as well as possibly levels of administered drugs or drug metabolites in specific brain regions in the setting of administration of drugs of abuse and/or potential treatment agents; 5) further studies of the endogenous opioid system of the gastrointestinal tract and its relationship to the brain in animal models, and basic clinical research studies of the use of an opioid antagonist with limited systemic bioavailability for the management of opioid induced gastrointestinal disorders; 6) Studies of the possible utility of the effects of the opioid antagonist nalmefene in the management of chronic alcoholism; and 7) continued prospective surveillance of the medical status of patients in methadone maintenance treatment, determining the changing patterns of hepatitis Beta, delta, and HIV-1 infection in this group, and also determination of the response to hepatitis Beta vaccination in former heroin addicts in methadone maintenance treatment, and studies of the events of early HIV-1 infection.